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The relationship between anaemia and malaria: Apparently simple, yet

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DOI: 10.1093/trstmh/tru012 · Source: PubMed

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Transactions of the Royal Society of Tropical Medicine and Hygiene Advance Access published January 31, 2014

Trans R Soc Trop Med Hyg

doi:10.1093/trstmh/tru012

The relationship between anaemia and malaria: apparently simple,

COMMENTARY
yet controversial
Francesco Castelli*, Giorgia Sulis and Silvio Caligaris

University Division of Infectious and Tropical Diseases, University of Brescia and Spedali Civili General Hospital, Brescia, Italy

*Corresponding author: Tel: +39 030 399 5664; E-mail: castelli@med.unibs.it

Received 31 December 2013; revised 9 January 2014; accepted 10 January 2014

Among many other factors, malaria plays a major causative role of anaemia globally. The mechanisms leading to

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anaemia in the course of malaria are extremely diverse, involving immunological factors that act differently
according to age and malaria epidemiology. The malaria-attributable fraction of anaemia may then differ in dif-
ferent settings. While tremendous efforts are being made to control malaria, the availability of a simple and reli-
able biomarker of impact is of the upmost importance. Promising data are accumulating that Hb levels could be
used as a proxy of malaria even in hypo-endemic areas, even if many grey areas still deserve research efforts.

Keywords: Anaemia, Biomarker, Malaria, Monitoring

Background suppression to iron delocalization.4 In holo-endemic malaria set-

Anaemia is a major contributor to disability and mortality, espe-
cially among children. Additionally, chronic anaemia in early child-
hood has been held responsible for poor developmental
performance. As the burden of anaemia-related diseases is par-
ticularly relevant in childhood, it is particularly worrying that
anaemia prevalence in children under 5 years of age is on the
rise, in contrast to all other age groups.1 Anaemia has many dif-
ferent causes, including food insecurity and nutritional deficien-
cies (poor intake of iron, folate, vitamin A and vitamin B12),
chronic and acute inflammation, parasitic infections (mainly mal-
aria and intestinal parasites), haemoglobinopathies (some linked
to malaria epidemiology) and other chronic conditions (e.g.
chronic kidney disease). The value of internationally recom-
mended standardized thresholds to classify anaemia2 is now
being questioned, since locally assessed reference intervals may
be more appropriate to reflect the health status of both the indi-
vidual and the population, especially in young children.3 For
example, Hb levels usually increase with altitude as a conse-
quence of increased erythropoiesis induced by low oxygen
tension.
Anaemia and malaria
Anaemia is common during clinical malaria attacks caused by all
Plasmodium species. In Plasmodium falciparum malaria, anaemia
has a multifactorial origin ranging from increased removal of
parasitized and unparasitized red blood cells (phagocytosis,
immune-mediated destruction, spleen sequestration) through
cytokine-mediated dyserythropoiesis and bone marrow
tings, up to one-third of asymptomatic children carrying parasites
may have low Hb levels. Furthermore, malarial anaemia often
coexists with, and is made worse by, other poverty related causes
of anaemia, such as malnutrition or intestinal parasites, in com-
plex interrelationships.5 Despite the additional clinical risk posed
by all-cause anaemia during P. falciparum malaria episodes, the
supplementation of iron in children living in malaria endemic
areas has been restrained by evidence that moderate iron defi-
ciency may play a protective role against severe P. falciparum
infection.6 This is possibly due to the iron depletion mechanism
in the acute phase of parasite invasion or to the predilection of
merozoites to invade young erythrocytes produced by
iron-induced erythropoiesis. Despite this, recent results of the
impact of iron fortification on malaria incidence in holo-endemic
malaria areas are, partly, reassuring.7
Anaemia as a proxy biomarker to monitor
changes in malaria epidemiology
As a consequence, assessment of Hb levels has been proposed as
a proxy for monitoring the impact of malaria control activities
[long-lasting insecticidal nets (LLIN), indoor residual spraying
(IRS), rapid diagnostic tests (RDTs) and artemisinin-combination
therapies (ACT)], in a given country due to the ease of testing in
the field.8 Because of the multifactorial nature of anaemia, this
approach is only sound where the malaria-attributable fraction
of anaemia is high, while its appropriateness in low malaria-
transmission areas has been matter of debate.
Using the large dataset from the Malaria Indicator Survey car-
ried out in Ethiopia in 2007, Reithinger and co-workers have

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F. Castelli et al.
assessed the risk factors for anaemia in 6054 children under 6
years of age living below 2500 m altitude, to investigate the
association between malaria and anaemia, and to discuss the
potential of using anaemia as a proxy indicator of malaria in a
hypo-endemic setting.9 The WHO standard thresholds for anae-
mia were used, without adjustments for altitude. The major find-
ings of the study were that anaemia was significantly associated
with male sex, younger age and, despite a low 1.7% parasite
prevalence rate, with reactivity to RDTs for malaria (P. falciparum
and Plasmodium vivax). Of interest, no association was found
between the presence of anaemia and altitude, wealth index,
urban/rural status, use of IRS and having slept under a net the pre-
vious night. The authors concluded that anaemia could poten-
tially be a useful proxy biomarker for malaria infections and for
malaria control in Ethiopia.
The paper is indeed interesting because its results, based on a
large nationwide dataset, support the use of Hb levels as a proxy
biomarker of malaria prevalence in low malaria-transmission set-
tings. However, there are few notes of caution which deserve con-
sideration. First, quite surprisingly, no correlation between Hb
levels and altitude were found. This paradox has already been
observed in high transmission malaria settings, where early
immunity in lowland populations may lead to low blood parasite
counts. In the paper by Reithinger et al., parasite blood counts
were not recorded and therefore could not be evaluated by
altitude strata. Second, malaria epidemiology in Ethiopia is geo-
graphically very heterogeneous, with large variations in transmis-
sion intensity. In fact, the prevalence of anaemia recorded
differed significantly among the sampled enumeration areas.
The results from the paper offer a nationwide picture, but they
may not be sensitive enough to identify regional differences in
the association of anaemia with malaria, as the sensitivity of
any surrogate biomarker varies according to the degree of overlap
(i.e. malaria-attributable fraction of anaemia) with the phenom-
enon it intends to measure. It has been recently reported that a
large proportion (35.6%) of anaemic children living at 2200 m alti-
tude in Ethiopia do not carry malaria parasites and, in contrast, as
many as 29.1% of malarious patients do not develop anaemia.
However, the association between malaria and anaemia was
stronger in children and women.3 Third, the impact of sub-
microscopic parasite carriers, as many as 29.4% of whom have
been reported to have anaemia,10 could not be identified by
Reithinger et al. without PCR techniques, leaving an area to be
investigated further. The overall specificity and sensitivity of mild-
moderate anaemia to reflect microscopic/RDT malaria infection is
quite poor. Fourth, the prevalence of intestinal parasites and hae-
moglobinopathies, the latter reportedly low in Ethiopia, was not
assessed.
In conclusion, the association between anaemia and malaria is
extremely complex in nature. The ease of Hb assessment under
field conditions is attractive and the paper by Reithinger and
co-workers provides additional evidence that such a surrogate
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marker may be useful to monitor malaria control progresses
even in low transmission settings. In these settings, however,
there is still field for research to properly integrate the many
variables in a valid and reproducible model.
Authors’ contributions: FC conceived the paper. All authors wrote, read
and approved the final manuscript. FC is the guarantor of the paper.
Funding: None.
Competing interests: None declared.
Ethical approval: Not required.
Downloaded from http://trstmh.oxfordjournals.org/ by guest on February 1, 2014
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